Diagnostic value of MUC4 immunostaining in distinguishing epithelial mesothelioma and lung adenocarcinoma

Llinares, Karine; Escande, Fabienne; Aubert, Sébastien; Buisine, Marie Pierre; Bolós, Carme de; Batra, Surinder K.; Gosselin, Bernard; Aubert, Jean; Porchet, Nicole; Copin, Marie Christine

doi:10.1038/modpathol.3800027

Cited by 60 publications

(45 citation statements)

References 48 publications

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“…Muc4 overexpression is frequently observed in numerous cancers, including pancreatic adenocarcinomas (38), where its expression is associated with metastatic phenotype (39), lung adenocarcinomas (40), intrahepatic cholangiocarcinoma mass-forming type where its co-expression with ErbB2 is correlated with short survival time (41), and non-small-cell lung cancer, where its expression is also associated with ErbB2 overexpression and early postoperative recurrence (42). Our observations suggest that Muc4 overexpression could contribute to tumor progression by augmenting PI3K activity through ErbB2/3 hyperactivation.…”

Section: Discussionmentioning

confidence: 99%

The Mucin Muc4 Potentiates Neuregulin Signaling by Increasing the Cell-surface Populations of ErbB2 and ErbB3

Funes

Miller

Lai

et al. 2006

Journal of Biological Chemistry

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Mucins provide a protective barrier for epithelial surfaces, and their overexpression in tumors has been implicated in malignancy. We have previously demonstrated that Muc4, a transmembrane mucin that promotes tumor growth and metastasis, physically interacts with the ErbB2 receptor tyrosine kinase and augments receptor tyrosine phosphorylation in response to the neuregulin-1␤ (NRG1␤) growth factor. In the present study we demonstrate that Muc4 expression in A375 human melanoma cells, as well as MCF7 and T47D human breast cancer cells, enhances NRG1␤ signaling through the phosphatidylinositol 3-kinase pathway. In examining the mechanism underlying Muc4-potetiated ErbB2 signaling, we found that Muc4 expression markedly augments NRG1␤ binding to A375 cells without altering the total quantity of receptors expressed by the cells. Cell-surface protein biotinylation experiments and immunofluorescence studies suggest that Muc4 induces the relocalization of the ErbB2 and ErbB3 receptors from intracellular compartments to the plasma membrane. Moreover, Muc4 interferes with the accumulation of surface receptors within internal compartments following NRG1␤ treatment by suppressing the efficiency of receptor internalization. These observations suggest that transmembrane mucins can modulate receptor tyrosine kinase signaling by influencing receptor localization and trafficking and contribute to our understanding of the mechanisms by which mucins contribute to tumor growth and progression.The ErbB family of receptor tyrosine kinases includes ErbB1/ epidermal growth factor (EGF) 3 receptor, ErbB2/Her2/Neu, ErbB3, and ErbB4. The EGF-like growth factor family of ligands binds the extracellular domain of the ErbB receptors leading to the formation of both homo-and heterodimers. Receptor dimer formation is followed by autophosphorylation of receptor intracellular domains, recruitment of intracellular signaling proteins, and the initiation of a number of signaling cascades that regulate cellular growth, motility, and survival. ErbB receptors play critical roles both in development and tissue maintenance (1), and their overexpression and aberrant activation have been implicated in the genesis and progression of a variety of human tumors (2).While in general receptor heterodimerization is thought to diversify ErbB signaling (1), heterodimerization with ErbB2 is required for ErbB3 signaling in response to the neuregulin-1 (NRG1) growth factor. No soluble growth factor ligand has been identified that binds to ErbB2, but it is the preferred dimerization partner of the other ErbB family members. Thus, it is thought that its function is to heterodimerize with the other ErbB family members to enhance signaling. ErbB3 is a binding receptor for NRG1 but lacks intrinsic kinase activity (3) and is not capable of signaling on its own. The ErbB2-ErbB3 heterodimer efficiently activates the Ras/Erk pathway, and the C-terminal domain of ErbB3 contains six binding sites for the p85 subunit of PI3K that very efficiently couple the activated receptor ...

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Section: Discussionmentioning

confidence: 99%

The Mucin Muc4 Potentiates Neuregulin Signaling by Increasing the Cell-surface Populations of ErbB2 and ErbB3

Funes

Miller

Lai

et al. 2006

Journal of Biological Chemistry

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“…The current study included a wide variety of primary sites of metastatic adenocarcinoma, including the biliary tract and prostate, which to the best of our knowledge has not been included in the previous studies [14,16,18]. The current series also included effusions into various body cavities, whereas the series by Llinares et al [14] focused on pleural effusions only.…”

Section: Discussionmentioning

confidence: 98%

“…Because MUC1 and MUC4 are expressed mainly by the epithelial cells and are frequently overexpressed in carcinoma cells, it would be reasonable to anticipate its applicability in discriminating MAC from both benign and malignant mesothelial cells. However, studies on the expression of these mucins in body cavity fluids are limited [13,14,15,16,17,18]. Using immunocytochemistry, Han et al [18] analyzed expression of MUC1 in formalin-fixed paraffin-embedded cell blocks prepared from effusion specimens with evidence of metastatic carcinoma.…”

Section: Discussionmentioning

confidence: 99%

“…MUC1 immunoreactivity was detected in all cases of pancreatic (9 of 9; 100%) and ovarian carcinomas (14 of 14; 100%). Llinares et al [14] recently analyzed MUC4 protein expression in a large number of pleural specimens (surgical resections and effusion cell blocks), including 41 malignant mesotheliomas, 32 cases of normal mesothelial cells or RMC, 45 lung adenocarcinomas and 21 non-pulmonary adenocarcinomas. None of the malignant mesotheliomas or normal or hyperplastic mesothelial cells reacted with the anti-MUC4 antibody.…”

Section: Discussionmentioning

confidence: 99%

“…However, studies on the expression of these mucins in body cavity fluids are limited [13,14,15,16,17,18]. Using immunocytochemistry, Han et al [18] analyzed expression of MUC1 in 25 effusion specimens with evidence of metastatic carcinoma including 14 ovarian serous carcinomas, 9 pancreatic carcinomas and 2 unknown primaries, and demonstrated that MUC1 immunoreactivity was detected in all cases of pancreatic and ovarian carcinoma.…”

Section: Introductionmentioning

confidence: 99%

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Diagnostic Usefulness of MUC1 and MUC4 for Distinguishing between Metastatic Adenocarcinoma Cells and Reactive Mesothelial Cells in Effusion Cell Blocks

Cho¹,

Kim²,

Lee³

et al. 2013

Acta Cytologica

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Objective: The aim of our study was to determine the diagnostic value of MUC1 and MUC4 for distinguishing between metastatic adenocarcinoma cells (MAC) and reactive mesothelial cells (RMC) in effusion fluids. Study Design: A total of 237 cell block specimens from pleural and peritoneal effusions, including 196 malignant effusions with MAC and 41 benign effusions with RMC, were stained with antibodies against MUC1 and MUC4. Membranous staining with or without cytoplasmic staining was considered to be positive. Results: MUC1 immunoreactivity was observed in 194 (99.0%) of 196 cases of MAC and in 20 (48.8%) of 41 cases of RMC. MUC4 immunoreactivity was observed in 174 (88.8%) of 196 cases of MAC and in 4 (9.8%) of 41 cases of RMC. For distinguishing MAC from RMC, the MUC1 reactivity was found to be 99.0% sensitive and 51.2% specific with a positive predictive value of 90.7% and a negative predictive value of 91.3%. The sensitivity of MUC4 for MAC was 88.8%, the specificity was 90.2%, the negative predictive value was 62.7%, and the positive predictive value was 97.8%. Conclusion: Our data suggest that MUC4 appears to be a sensitive and specific marker for differentiating between MAC and RMC.

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Current status of mucins in the diagnosis and therapy of cancer

et al. 2009

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Mucins are the most abundant high molecular weight glycoproteins in mucus. Their nature and glycosylation content dictates the biochemical and biophysical properties of viscoelastic secretions, pointing out an important role in diverse biological functions, such as differentiation, cell adhesions, immune responses, and cell signaling. Mucins are expressed in tubular organs by specialized epithelial cells in the body. Their aberrant expression is well documented in a variety of inflammatory or malignant diseases. From a prognosis point of view, their expression and alterations in glycosylation are associated with the development and progression of malignant diseases. Therefore, mucins can be used as valuable markers to distinguish between normal and disease conditions. Indeed, this alteration in glycosylation patterns generates several epitopes in the oligosaccharide side chains that can be used as diagnostic and/or prognostic markers. Furthermore, these characteristic tumor-associated epitopes are extensively used as appropriate immunotargets of malignant epithelial cells. Therefore, in an effort to detect and treat cancer at the earliest stage possible, mucins are analyzed as potential markers of disease for diagnosis, progression, and for therapeutic purposes. In this review, we focused on the current status of the distribution of mucins in normal and pathologic conditions and their clinical use both in cancer diagnosis and therapeutics treatments.

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Diagnostic value of MUC4 immunostaining in distinguishing epithelial mesothelioma and lung adenocarcinoma

Cited by 60 publications

References 48 publications

The Mucin Muc4 Potentiates Neuregulin Signaling by Increasing the Cell-surface Populations of ErbB2 and ErbB3

The Mucin Muc4 Potentiates Neuregulin Signaling by Increasing the Cell-surface Populations of ErbB2 and ErbB3

Diagnostic Usefulness of MUC1 and MUC4 for Distinguishing between Metastatic Adenocarcinoma Cells and Reactive Mesothelial Cells in Effusion Cell Blocks

Current status of mucins in the diagnosis and therapy of cancer

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